miR‑146a regulates the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF‑κB signaling by targeting TRAF6

Li,Tian; Li,Mengxiong; Xu,Chengfang; Xu,Xiaoyu; Ding,Jie; Cheng,Li; Ou,Rongying

doi:10.3892/or.2019.7046

miR‑146a regulates the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF‑κB signaling by targeting TRAF6

Authors:
- Tian Li
- Mengxiong Li
- Chengfang Xu
- Xiaoyu Xu
- Jie Ding
- Li Cheng
- Rongying Ou
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, The Seventh Affiliated Hospital of Sun Yat‑sen University, Shenzhen, Guangdong, P.R. China, Department of Obstetrics, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong, P.R. China, Department of Gynecology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong, P.R. China, Department of Gynecology and Obstetrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China
Published online on: March 7, 2019 https://doi.org/10.3892/or.2019.7046
Pages: 2897-2908

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to investigate whether miRNA‑146a regulated the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis. miR‑146a expression was increased in human cervical cancer. Both overall survival (OS) and disease‑free survival (DFS) of low miR‑146a expression were higher than those of high miR‑146a expression. Additionally, IL‑17a expression was lower in patients with high miR‑146a expression compared to that of patients with lower miR‑146a expression. In a co‑culture of cervical cancer and CD4+ T cells, downregulation of miR‑146a inhibited cell growth and induced apoptosis of cervical cancer cells, while overexpression of miR‑146a promoted cell growth and reduced apoptosis of cervical cancer cells. Downregulation of miR‑146a induced TRAF6 and NF‑κB protein expression, increased IL‑6, IL‑17A and IL‑21 levels, and enhanced p‑STAT3 protein expression. The inhibition of TRAF6 attenuated the effects of anti‑miR‑146a on the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis. Collectively, miR‑146a regulated the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF‑κB signaling by targeting TRAF6. miR‑146a may function as an oncogene in cervical cancer via Th17 cell differentiation by targeting TRAF6.

View Figures

View References

1	Tsunoda AT, Marnitz S, Soares Nunes J, Mattos de Cunha Andrade CE, Scapulatempo Neto C, Blohmer JU, Herrmann J, Kerr LM, Martus P, Schneider A, et al: Incidence of histologically proven pelvic and Para-aortic lymph node metastases and rate of upstaging in patients with locally advanced cervical cancer: Results of a prospective randomized trial. Oncology. 92:213–220. 2017. View Article : Google Scholar : PubMed/NCBI
2	de Azevedo C, Thuler LCS, de Mello MJG, de Oliveira Lima JT, da Fonte ALF, Fontão DFS, Carneiro VCG, Chang TMC and Ferreira CG: Phase II trial of neoadjuvant chemotherapy followed by chemoradiation in locally advanced cervical cancer. Gynecol Oncol. 146:560–565. 2017. View Article : Google Scholar : PubMed/NCBI
3	Matijevic M, Hedley ML, Urban RG, Chicz RM, Lajoie C and Luby TM: Immunization with a poly (lactide co-glycolide) encapsulated plasmid DNA expressing antigenic regions of HPV 16 and 18 results in an increase in the precursor frequency of T cells that respond to epitopes from HPV 16, 18, 6 and 11. Cell Immunol. 270:62–69. 2011. View Article : Google Scholar : PubMed/NCBI
4	Varghese VK, Shukla V, Kabekkodu SP, Pandey D and Satyamoorthy K: DNA methylation regulated microRNAs in human cervical cancer. Mol Carcinog. 57:370–382. 2018. View Article : Google Scholar : PubMed/NCBI
5	Shishodia G, Verma G, Das BC and Bharti AC: miRNA as viral transcription tuners in HPV-mediated cervical carcinogenesis. Front Biosci. 10:21–47. 2018. View Article : Google Scholar
6	Liang C, Ding J, Yang Y, Deng L and Li X: MicroRNA-433 inhibits cervical cancer progression by directly targeting metadherin to regulate the AKT and β-catenin signalling pathways. Oncol Rep. 38:3639–3649. 2017.PubMed/NCBI
7	Hou F, Li Z, Ma D, Zhang W, Zhang Y, Zhang T, Kong B and Cui B: Distribution of Th17 cells and Foxp3-expressing T cells in tumor-infiltrating lymphocytes in patients with uterine cervical cancer. Clin Chim Acta. 413:1848–1854. 2012. View Article : Google Scholar : PubMed/NCBI
8	Yu Q, Lou XM and He Y: Preferential recruitment of Th17 cells to cervical cancer via CCR6-CCL20 pathway. PLoS One. 10:e01208552015. View Article : Google Scholar : PubMed/NCBI
9	Zhang W, Tian X, Mumtahana F, Jiao J, Zhang T, Croce KD, Ma D, Kong B and Cui B: The existence of Th22, pure Th17 and Th1 cells in CIN and cervical cancer along with their frequency variation in different stages of cervical cancer. BMC Cancer. 15:7172015. View Article : Google Scholar : PubMed/NCBI
10	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
11	Wakatsuki M, Kato S, Ohno T, Karasawa K, Kiyohara H, Tamaki T, Ando K, Tsujii H, Nakano T, Kamada T, et al: Clinical outcomes of carbon ion radiotherapy for locally advanced adenocarcinoma of the uterine cervix in phase 1/2 clinical trial (protocol 9704). Cancer. 120:1663–1669. 2014. View Article : Google Scholar : PubMed/NCBI
12	Sewali B, Okuyemi KS, Askhir A, Belinson J, Vogel RI, Joseph A and Ghebre RG: Cervical cancer screening with clinic-based Pap test versus home HPV test among Somali immigrant women in Minnesota: A pilot randomized controlled trial. Cancer Med. 4:620–631. 2015. View Article : Google Scholar : PubMed/NCBI
13	Wang X, Tang S, Le SY, Lu R, Rader JS, Meyers C and Zheng ZM: Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS One. 3:e25572008. View Article : Google Scholar : PubMed/NCBI
14	He X, Zheng Y, Liu S, Shi S, Liu Y, He Y, Zhang C and Zhou X: MiR-146a protects small intestine against ischemia/reperfusion injury by down-regulating TLR4/TRAF6/NF-kappaB pathway. J Cell Physiol. 233:2476–2488. 2018. View Article : Google Scholar : PubMed/NCBI
15	Tristão FS, Rocha FA, Carlos D, Ketelut-Carneiro N, Souza COS, Milanezi CM and Silva JS: Th17-inducing cytokines IL-6 and IL-23 are crucial for granuloma formation during experimental paracoccidioidomycosis. Front Immunol. 8:9492017. View Article : Google Scholar : PubMed/NCBI
16	Li B, Wang X, Choi IY, Wang YC, Liu S, Pham AT, Moon H, Smith DJ, Rao DS, Boldin MP, et al: miR-146a modulates autoreactive Th17 cell differentiation and regulates organ-specific autoimmunity. J Clin Invest. 127:3702–3716. 2017. View Article : Google Scholar : PubMed/NCBI
17	Yoon JH, Sudo K, Kuroda M, Kato M, Lee IK, Han JS, Nakae S, Imamura T, Kim J, Ju JH, et al: Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in T_H17 differentiation. Nat Commun. 6:76002015. View Article : Google Scholar : PubMed/NCBI
18	Lee SY, Lee SH, Yang EJ, Kim JK, Kim EK, Jung K, Jung H, Lee K, Lee HH, Lee BI, et al: Coenzyme Q10 inhibits Th17 and STAT3 signaling pathways to ameliorate colitis in mice. J Med Food. 20:821–829. 2017. View Article : Google Scholar : PubMed/NCBI
19	Lee SH, Park JS, Byun JK, Jhun J, Jung K, Seo HB, Moon YM, Kim HY, Park SH and Cho ML: Corrigendum: PTEN ameliorates autoimmune arthritis through down-regulating STAT3 activation with reciprocal balance of Th17 and Tregs. Sci Rep. 7:422672017. View Article : Google Scholar : PubMed/NCBI
20	Betts BC, Sagatys EM, Veerapathran A, Lloyd MC, Beato F, Lawrence HR, Yue B, Kim J, Sebti SM, Anasetti C, et al: CD4⁺ T cell STAT3 phosphorylation precedes acute GVHD, and subsequent Th17 tissue invasion correlates with GVHD severity and therapeutic response. J Leukoc Biol. 97:807–819. 2015. View Article : Google Scholar : PubMed/NCBI
21	Zhou T, Lin H, Cheng Z, Ji C, Zhang C and Tian J: Mechanism of microRNA-146a-mediated IL-6/STAT3 signaling in lumbar intervertebral disc degeneration. Exp Ther Med. 14:1131–1135. 2017. View Article : Google Scholar : PubMed/NCBI
22	Qu N, Xu M, Mizoguchi I, Furusawa J, Kaneko K, Watanabe K, Mizuguchi J, Itoh M, Kawakami Y and Yoshimoto T: Pivotal roles of T-helper 17-related cytokines, IL-17, IL-22, and IL-23, in inflammatory diseases. Clin Dev Immunol. 2013:9685492013. View Article : Google Scholar : PubMed/NCBI
23	Wang J, Xu K, Wu J, Luo C, Li Y, Wu X, Gao H, Feng G and Yuan BZ: The changes of Th17 cells and the related cytokines in the progression of human colorectal cancers. BMC Cancer. 12:4182012. View Article : Google Scholar : PubMed/NCBI
24	Wan CK, Andraski AB, Spolski R, Li P, Kazemian M, Oh J, Samsel L, Swanson PA II, McGavern DB, Sampaio EP, et al: Opposing roles of STAT1 and STAT3 in IL-21 function in CD4⁺ T cells. Proc Natl Acad Sci USA. 112:9394–9399. 2015. View Article : Google Scholar : PubMed/NCBI
25	Halwani R, Sultana A, Vazquez-Tello A, Jamhawi A, Al-Masri AA and Al-Muhsen S: Th-17 regulatory cytokines IL-21, IL-23, and IL-6 enhance neutrophil production of IL-17 cytokines during asthma. J Asthma. 54:893–904. 2017. View Article : Google Scholar : PubMed/NCBI
26	Ye EA and Steinle JJ: miR-146a suppresses STAT3/VEGF pathways and reduces apoptosis through IL-6 signaling in primary human retinal microvascular endothelial cells in high glucose conditions. Vision Res. 139:15–22. 2017. View Article : Google Scholar : PubMed/NCBI